Iatrogenic hypoglycemia is the most serious acute complication in intensively insulin-treated diabetes and it remains the limiting factor in maintaining proper glycemic control. The brain, and especially the ventromedial hypothalamus (VMH), plays a crucial role in sensing hypoglycemia and in initiating the physiological counterregulatory responses that correct it. However, both reoccurring exposure to hypoglycemia and longstanding diabetes can impair the mechanisms that normally correct hypoglycemia. This research proposal addresses whether diabetes and antecedent hypoglycemia alter brain fuel metabolism in a manner that prevents it from properly sensing falling blood glucose levels. The long-term objectives of this research are to understand how the brain senses changes in blood glucose levels, how it communicates these signals to peripheral organs to initiate counterregulatory responses and why these mechanisms are impaired with antecedent hypoglycemia and in diabetes. It is essential that we achieve a better understanding of how the body detects and activates defense mechanisms against hypoglycemia so that appropriate therapies can be developed to more effectively prevent hypoglycemia outcomes in diabetic patients. If proven successful, these studies could potentially reveal new therapeutic targets for the development of insulin co-therapies.